Sphingolipid Synthesis via Olefin Cross Metathesis: Preparation of a Differentially Protected Building Block and Application to the Synthesis of D-erythro-Ceramide Anand Narain Rai and Amit Basu* Chemistry Department, Brown UniVersity Box H, ProVidence, Rhode Island 02912 abasu@brown.edu Received May 4, 2004 ABSTRACT The sphingolipid backbone is readily assembled by E-selective olefin cross metathesis of a suitable building block. Sphingolipids are an important class of natural products found in abundance in eukaryotic cell membranes. 1 Varia- tions in sphingolipid structure occur both at the N-acyl moiety and at the group attached to the primary alcohol, which is usually a phosphate, a phosphatidyl choline, or a carbohy- drate. Additional skeletal diversity in the main carbon chain has also been identified. 2 Sphingolipids are involved in molecular recognition processes at the cell membrane and are important components of lipid rafts and influence cell signaling events at the membrane. As a result of our interest in glycosphingolipid recognition processes, we sought a general synthetic route to sphingolipids that would allow systematic variation of both the O- and N-linked function- alities, as well as the identity of the main carbon chain. 3 In practice, this requires the preparation of a building block such as I, which contains all of the conserved and requisite functionality differentiated with orthogonal protecting groups. 4 In this paper we report an approach to sphingolipid synthesis in which the main carbon chain is installed via a highly stereoselective olefin cross metathesis reaction. 5 (1) (a) Brodesser, S.; Sawatzki, P.; Kolter, T. Eur. J. Org. Chem. 2003, 2021-2034. (b) Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532-1568. (2) (a) Alam, N.; Wang, W. H.; Hong, J. K.; Lee, C. O.; Im, K. S.; Jung, J. H. J. Nat Prod. 2002, 65, 944-945. (b) Inagaki, M.; Nakamura, K.; Kawatake, S.; Higuchi, R. Eur. J. Org. Chem. 2003, 325-331; Ojika, M.; Yoshino, G.; Sakagami, Y. Tetrahedron Lett. 1997, 38, 4235-4238. (3) For some recent syntheses of ceramide/sphingolipids, see: (a) Jeong, I.-Y.; Lee, J. H.; Lee, B. W.; Kim, J. H.; Park, K. H. Bull. Korean Chem. Soc. 2003, 24, 617-622. (b) Milne, J. E.; Jarowicki, K.; Kocienski, P. J.; Alonso, J. Chem. Commun. 2002, 426-427. (c) Lees, W. J.; Gargano, J. M. Tetrahedron Lett. 2001, 42, 5845-5847. (d) Lee, J.-M.; Lim, H.-S.; Chung, S.-K. Tetrahedron: Asymmetry 2002, 13, 343-347. (e) Bittman, R.; Chun, J.; Li, G.; Byun, H.-S. Tetrahedron Lett. 2002, 43, 375-377. For recent reviews of sphingolipid syntheses, see: (f) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075-1091. (g) Curfman, C.; Liotta, D. Methods Enzymol. 1999, 311, 391-457. (4) Gargano and Lees have reported the preparation of an orthogonally protected sphingosine with the main carbon chain already installed; See ref 3c. ORGANIC LETTERS 2004 Vol. 6, No. 17 2861-2863 10.1021/ol049183a CCC: $27.50 © 2004 American Chemical Society Published on Web 07/28/2004